RGS PROTEIN FUNCTION IN CARDIAC PHYSIOLOGY

RGS 蛋白在心脏生理学中的功能

• 批准号: 6195819
• 负责人: ANTHONY JUSTIN MUSLIN
• 金额: $ 24.89万
• 依托单位: BARNES-JEWISH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6195819
• 关键词: biological signal transduction; cardiac myocytes; cell growth regulation; cell morphology; congestive heart failure; disease /disorder model; gene mutation; guanosinetriphosphatase activating protein; heart function; human tissue; laboratory mouse; laboratory rat; newborn animals; tissue /cell culture; ventricular hypertrophy

Postnatal mammalian cardiomyocytes respond to mechanical stress, growth factor and hormonal action, and metabolic abnormalities by enlarging, but these cells are unable to proliferate for reasons that are not understood. The clinical consequences of human cardiac hypertrophy are very significant and include the development of serious cardiac arrhythmias, of diastolic dysfunction that can result in pulmonary edema and fluid overload, and of congestive heart failure. Intracellular signaling cascades play a major role in the development of cardiac hypertrophy. Several lines of evidence support the role of G proteins in the development of cardiac hypertrophy. RGS (regulator of G protein signaling) proteins were recently found to be GTPase activating proteins (GAPs) for heterotrimeric G proteins. In this proposal, we will outline experiments to test the hypothesis that RGS proteins determine the responsiveness of cardiomyocytes to extracellular stimuli, and that RGS gene expression can be increased as an adaptive mechanism to limit G- protein-mediated signal transduction. We will examine the expression pattern of RGS family members in animal models of cardiac hypertrophy and congestive heart failure. We will determine the relative ability of RGS family members to block cardiomyocyte signal transduction and hypertrophic growth. We will determine whether RGS4 inhibits cardiac hypertrophy in a transgenic mouse model in response to provocative stimuli. Finally, we will determine whether dominant negative mutant forms of RGS2 and RGS4 promote cardiomyocyte signal transduction and hypertrophic growth. These experiments will help to establish the role of RGS proteins in the pathophysiology of cardiac hypertrophy and may have an impact on future treatment of patients with this disorder and those in whom hypertrophy has progressed to heart failure.

产后哺乳动物心肌细胞对机械应力，生长因子和激素作用以及代谢异常的反应，但由于尚不清楚的原因，这些细胞无法增殖。 人类心脏肥大的临床后果非常重要，包括出现严重的心律不齐，舒张功能障碍的发展，这些功能可能导致肺水肿和液体超负荷以及充血性心力衰竭。 细胞内信号传导级联反应在心脏肥大的发展中起主要作用。 几条证据支持G蛋白在心脏肥大发展中的作用。 最近发现RGS（G蛋白信号传导的调节剂）蛋白是杂点聚合物G蛋白的GTPase激活蛋白（GAP）。 在该提案中，我们将概述实验，以测试RGS蛋白决定心肌细胞对细胞外刺激的反应性的假设，并且可以增加RGS基因表达作为限制G-蛋白介导的信号转导的一种适应性机制。 我们将检查RGS家族成员在心脏肥大和充血性心力衰竭的动物模型中的表达模式。 我们将确定RGS家族成员阻止心肌细胞信号转导和肥厚性生长的相对能力。 我们将确定RGS4是否响应挑衅性刺激而抑制转基因小鼠模型中的心脏肥大。最后，我们将确定RGS2和RGS4的主要负突变形式是否促进心肌细胞信号转导和肥厚性生长。 这些实验将有助于确定RGS蛋白在心脏肥大的病理生理学中的作用，并可能对这种疾病患者的未来治疗以及肥大症已发展为心脏衰竭的患者。